The prevalence of type 2 diabetes is increasing as the incidence of childhood obesity rises.1,2 Metformin is the only oral agent with FDA approval for the management of type 2 diabetes in adolescents, and insulin can be added if oral therapy fails to achieve treatment targets. Guidelines on lifestyle modification in adolescent patients with type 2 diabetes are extrapolated from studies completed in adult populations as there is little data evaluating the efficacy of lifestyle modification in the pediatric population and there is no data comparing the effectiveness of lifestyle modification to pharmacotherapy in this population.1,2
The TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) study group enrolled 699 adolescents age 10 to 17 years within 2 years of their diagnosis to evaluate the glycemic durability of metformin (1000mg twice daily), metformin plus lifestyle modification (M+L) and metformin plus rosiglitazone (4mg twice daily, M+R).3 Eligible patients (n=927) underwent a 2-6 month run-in period and if an A1C <8% was reached on metformin alone, they were randomly assigned to one of the three interventions. The lifestyle modification focused on weight loss through family-based intervention to support changes in eating habits and activity. The primary outcome was to compare the treatment groups based on the time to treatment failure, defined as a persistently elevated A1c level (>8%) or a persistent decompenstation in metabolic control requiring insulin therapy.
Patients had a mean duration of diabetes of 7.8 months and were followed for an average of 3.86 years. The primary outcome occurred in 51.7% of patients on metformin alone, 46.6% of patients managed with M+L and 38.6% of the patients on M+R. M+R was found to statistically decrease the occurrence of the primary outcome by 25.3% compared to metformin alone (p=0.006); however, M+L was not found to significantly differ from either metformin alone or combination therapy with rosiglitazone. It was found that M+R was more effective in girls compared to boys, and overall failure rates were the highest in non-Hispanic black patients. The median time to treatment failure for all groups was 11.5 months, and there was not a difference between groups in terms of time to primary outcome.4 While the occurrence of serious adverse events was reported to be the highest in the M+L group, it was found that 87% of reported serious adverse events were not considered to be due to study treatment. Overall, adverse events were considered equivalent between the three treatment groups except fewer patients in the M+R group experienced increases in liver enzymes. At 24 months, the change in percent of overweight patients was 0.89 percentage points for M+R, -1.42 for metformin alone and -5.02 for M+L group (P<0.001 for both comparisons with MR). A decrease of 7 percentage points in the percent overweight was considered meaningful; more individuals in the M+L (31.2%) reached a meaningful weight lose compared to metformin alone (24.3%) and M+R (16.7%). The authors concluded, within a few years of diagnosis combination therapy or insulin therapy will be necessary to meet glycemic goals for the majority of adolescents with type 2 diabetes. While M+R have a lower failure rate compared to metformin monotherapy, it caused a modest increase in BMI and fat mass. In addition, the authors caution the reader to interpret the data related to lack of increased adverse events associated with rosiglitazone carefully due to the small sample size of the treatment group. This trial does not elucidate the risk of decreased bone density in a population that typically experiences significant skeletal growth, nor does it provide information on the long-term impact on cardiac outcomes in this young population.
One concern this study highlights is the fact that the failure rates for metformin monotherapy were higher in this adolescent population compared to previously reported failure rates in adult populations.5,6 The reason for this difference is not known as it is currently believed that the pathophysiology of type 2 diabetes is similar in the two populations.2 In one trial, nearly 99% of adult patients were taking maximum doses of metformin;6 however, the percentage of adolescents on maximal dose of metformin was not reported by the TODAY study group. In addition, higher baseline A1c was associated with treatment failure in ...